Overview of pediatric bone problems and related osteoporosis.

Osteoporosis is a well-established clinical problem in adults. Osteoporosis in pediatrics, on the other hand, is a new and evolving area, with certain unique diagnostic and clinical challenges. Recently, there has been an increased awareness of osteoporosis in children, both as a primary problem due to genetic mutations and enzyme deficiencies, and as secondary to various diseases, medications, and lifestyle issues. In this review we discuss the common forms of osteoporosis, including candidate genes, mutations of which can lead to primary osteoporosis, the mechanisms involved in the pathogenesis of secondary bone loss, and possible ways of diagnosing, preventing, or treating these conditions. The purpose of the article is to provide a summary of our current knowledge of pediatric bone problems and to provide a basis for discussion of the most appropriate ways to detect, treat, or prevent such problems.

The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn.

BACKGROUND: The hypermetabolic response to burn increases protein catabolism. Euglycemic hyperinsu-linemia with exogenous insulin maintains muscle protein by continued stimulation of net protein synthesis. Our aim was to determine the effect of euglycemic hyperinsulinemia over the entire hospitalization on muscle anabolism by investigating lean body mass (LBM) as the primary endpoint. METHODS: Eighteen subjects between the ages of 2 and 18 with burns of more than 40% were prospectively randomized into 2 groups, a control (n = 9) and a treatment group (n = 9). The treatment group was given continuous intravenous insulin at a rate of at least 1.5 microU/kg/min to maintain serum glucose levels between 100 to 140 mg/dL. Treatment was instituted 24 to 48 hours after arrival and continued until the patient's injury was 95% healed. All patients received continuous enteral feeding. Patients underwent body composition studies by dual-energy x-ray absorptiometry (DEXA) scan on postoperative day 6 after initial burn excision and when 95% healed. RESULTS: Nutritional intakes were not different between groups. In the control, subjects continued catabolism resulted in peripheral muscle wasting and centripetal obesity with diminished truncal LBM. The treatment group had improvement in lean body mass (P =.004) and bone mass (P =.025). The treatment group also had less peripheral muscle wasting with overall increases in upper/lower extremity LBM (P =.005). Hospital length of stay in days per percent of total body surface area burned was decreased in the insulin group (control = 1.03 +/- 0.1 vs 0.7 +/- 0.9 for insulin patients; P <.05). CONCLUSIONS: Euglycemic hyperinsulinemia throughout the hospital course mitigates muscle catabolism and preserves lean body mass.

Persistent hypoparathyroidism following magnesium repletion in burn-injured children.

Children suffering severe burns develop hypocalcemia, magnesium (Mg) depletion, hypoparathyroidism, and renal resistance to parathyroid hormone (PTH) infusion. We hypothesized that Mg depletion accounted for both the hypoparathyroidism and the renal resistance to PTH, and that Mg repletion would improve both. Due to a lack of PTH for infusion, we studied only the effect of Mg repletion on the relationship between ionized Ca (iCa) and PTH in the serum of 14 sequentially recruited children burned > or =40% total body surface area. All received a urinary Mg retention test a median of 20 days post burn (range 8-137 days). Seven (50%) of the children remained Mg depleted, which was not attributable to burn size or to time from burn to study. Combined enteral and parenteral Mg intakes were not different between the depleted and repleted groups, 12.2+/-4.4 (SD) mg/kg per day and 14.2+/-6.2 mg/kg per day, respectively. Both groups had low intact PTH levels in relation to serum iCa concentration, indicating persistent hypoparathyroidism. We conclude that Mg depletion is not the chief cause of hypoparathyroidism following thermal injury and we postulate that the persistent hypoparathyroidism is consistent with a reduced set-point for Ca suppression of PTH secretion.

Up-regulation of the parathyroid calcium-sensing receptor after burn injury in sheep: a potential contributory factor to postburn hypocalcemia.

OBJECTIVE: To test the hypothesis that the hypocalcemia and hypoparathyroidism that follow severe burn injury are related to up-regulation of the parathyroid gland calcium-sensing receptor (CaR), which may reduce the set-point for suppression of circulating parathyroid hormone by blood calcium. DESIGN: A controlled but unblinded study. SETTING: An investigational intensive care unit. SUBJECTS: Female range ewes. INTERVENTION: Sheep were subjected to a 40% total body surface area burn under anesthesia (n = 9) or sham burn receiving anesthesia and fluid resuscitation only (n = 8) and were killed 48 hrs postburn. MEASUREMENTS AND RESULTS: Blood ionized calcium, magnesium, and creatinine, and urinary calcium, magnesium, and creatinine were monitored for 48 hrs. After the sheep were killed, parathyroids (burn group, n = 3; sham group, n = 4) and kidneys (n = 4, each group) were harvested, snap frozen in liquid nitrogen, and analyzed for CaR messenger ribonucleic acid (mRNA) by Northern blot, and were analyzed for CaR cell-surface staining by immunocytochemistry with a polyclonal CaR-specific antiserum (parathyroids only). Bumed sheep were hypocalcemic and hypomagnesemic compared with sham-burned control sheep. CaR mRNA was increased by 50% (p < 0.005, analysis of variance) with a corresponding increase in the intensity of CaR immunoreactivity associated with the cell surface in parathyroids obtained from burned (n = 3) compared with sham-burned (n = 2) sheep. These findings are consistent with up-regulation of the parathyroid CaR and a related decrease in set-point for calcium suppression of parathyroid hormone secretion that may contribute to the previously reported postburn hypoparathyroidism and hypocalcemia.

Bone turnover in preterm infants.

Total parenteral nutrition is associated with osteopenia in preterm infants. Insufficient calcium and phosphate are likely causes: aluminum contamination is another possible contributing factor as this adversely affects bone formation and mineralization. The study was designed to evaluate changes in biochemical markers of bone turnover in 22 preterm infants receiving total parenteral nutrition in comparison with 19 term infants. We collected urine and serum samples from 22 preterm infants, mean gestational age 29 wk, within 48 h and again at 3 wk of life. We also collected urine samples from 19 term infants, mean gestational age 39 wk, during the first day of life. Bone resorption was assessed by the measurement of urinary pyridinium cross-links by HPLC and ELISA and the N-telopeptide of type I collagen by ELISA. Bone formation was assessed in premature infants by the measurement of serum osteocalcin. The N-telopeptide of type I collagen was higher in the preterm infants compared with term at baseline (p < 0.01). There was no difference between the pyridinium cross-links in the preterm and term infants. All the biochemical markers of bone turnover increased significantly in the preterm infants during the first 3 wk of life, e.g. N-telopeptide was a 153% change from baseline (p < 0.001). Aluminum in the total parenteral nutrition solutions did not cause a decrease in bone formation at the level administered (3-6 microg, 0.1-0.2 micromol x kg(-1) x d(-1)).

The role of bone densitometry in the diagnosis and management of the severely burned patient with bone loss.

Children and adults who suffer severe burn injuries develop abnormalities in bone and mineral metabolism. The most prominent of these is a reduction in bone formation. Events occurring immediately following burn injury that are likely contributors to the reduced bone formation include an increase in endogenous glucocorticoid production, functional growth hormone deficiency, hypoparathyroidism, and interoperative immobilization. The proinflammatory cytokines interleukin-1 beta and interleukin-6 may also contribute. To date, the effects of burn injury on bone formation have been equivocal. However, the major reduction in bone formation without any consistent change in resorption suggests an uncoupling of formation and resorption. A consequence of this is lumbar spine bone loss as detected by dual-energy X-ray absorptiometry by 6 wk postburn. In both cross-sectional and longitudinal studies, the initial low bone density remains decreased in relation to unburned age-matched peers. The reduced bone density increases the risk for postburn fractures and for reduced peak bone mass, increasing the risk of these patients for adult-onset osteoporosis.

Ciprofloxacin as a therapeutic modality in pediatric burn wound infections: efficacious or contraindicated?

BACKGROUND: Food and Drug Administration regulations state that ciprofloxacin hydrochloride may cause arthropathies. For this reason, such therapy is contraindicated in the pediatric population. However, several studies in children with cystic fibrosis have found the drug to be efficacious. Our hypothesis was that ciprofloxacin treatment is justified in the case of multiresistant organisms in burn populations. DESIGN: During a 4-year period (January 1, 1993, to December 31, 1997) we treated 56 of our pediatric burn patients with ciprofloxacin when cultures proved resistant to other antibiotics. The burn area was 65% of the total body surface area. The average patient age was 8.4 years. Of the 56 patients who received ciprofloxacin, 50 received the recommended dose. Biopsy specimens were assessed for quantitative bacteriology and antibiotic sensitivity. Radiologic review was conducted to examine for arthropathy. RESULTS: All patients showed unequivocal reduction in quantitative bacterial counts, and susceptibility to ciprofloxacin remained stable without the development of resistance. Of the 56 patients treated, 42 had a major reduction in their quantitative wound biopsies from 10(6) to less than 100 colonies per gram of tissue, while the remaining 14 were observed to have a 2- to 3-log decrease. No arthropathy was detected in any of the 56 patients receiving ciprofloxacin. Review of the patients' charts showed no documented adverse events associated with the use of ciprofloxacin. All patients survived their thermal injury and the complications associated with it without any untoward problems or complications of arthropathy. CONCLUSION: On the basis of these data, ciprofloxacin therapy in the treatment of immunosuppressed pediatric burn patients is efficacious and does not cause arthropathy.

Magnesium deficit in major burns: role in hypoparathyroidism and end-organ parathyroid hormone resistance.

Children and adults who are severely burned develop magnesium(Mg) depletion, hypocalcemia, hypoparathyroidism and renal resistance to the administration of exogenous parathyroid hormone(PTH). This same spectrum of findings is seen with both Mg depletion and hypermagnesemia. We reported that in a group of ten children burned at least 30 per cent of total body surface area that 70-80 per cent of serum levels of ionized calcium and Mg were low. In three of the patients studies when serum Mg returned to normal, retention of a standard Mg infusion was abnormally high in two of them, suggesting persistence of Mg depletion despite normal serum Mg levels. Mg intake in these children conforms to the recommended dietary intake for age suggesting that excessive Mg losses may contribute to the observed Mg depletion. These losses are through the burn wound and possibly through abnormal intestinal secretion. Increased metabolic rate seen in burn patients may also promote intracellular Mg uptake to support the increased energy requirements of cells. It is hypothesized that since Mg is an important cofactor in the production of cyclic AMP, Mg deficiency may block intracellular cyclic AMP generation in parathyroid cells to block the secretion of parathyroid hormone and in renal tubular cells to block the renal generation may improve PTH secretion and hypocalcemia in non-burned patients, preliminary data in burned children suggest that the cause of hypocalcemia and hypoparathyroidism is more complex.

Ciprofloxacin versus cefuroxime axetil in the treatment of adult patients with acute bacterial sinusitis.

OBJECTIVE: This study compared the use and efficacy of ciprofloxacin to cefuroxime axetil for adult patients with acute bacterial sinusitis. METHOD: We conducted a prospective, randomized, double-blind pilot study of oral ciprofloxacin (500 mg twice daily) versus cefuroxime axetil (250 mg twice daily) for 2 to 3 weeks in the treatment of adult patients with a clinical diagnosis of acute bacterial maxillary sinus infections or acute exacerbation of chronic bacterial sinusitis. Patients with microbiologically and radiologically confirmed sinusitis infection composed the efficacy population. RESULTS: Of the 83 patients enrolled, 13 of 42 (31%) ciprofloxacin- and 19 of 41 (46%) cefuroxime axetil-treated patients had a respiratory pathogen isolated from a sinus aspiration. The most frequent pretherapy isolated included Haemophilus influenzae (11), streptococcus species (20), staphylococcus species (7), Proteus mirabilis (3), and Neisseria sicca (3). At the end of therapy, clinical resolution or improvement in efficacy-valid patients was achieved in 12 (100%) ciprofloxacin-treated patients and in 14 (74%) cefuroxime axetil recipients. The five (26%) cefuroxime axetil clinical failures were due to development of superinfection. Bacteriologic eradication occurred in 12 (100%) and 14 (100%) ciprofloxacin and cefuroxime axetil patients, respectively. Similar clinical and bacteriologic response rates were observed at the 2- to 4-week follow-up. Among 83 intent-to-treat patients, 19 (45%) ciprofloxacin and 14 (34%) cefuroxime axetil patients had drug-related adverse events. The most common adverse event in both treatment groups was gastrointestinal. CONCLUSION: This pilot study suggests that ciprofloxacin is efficacious in the management of acute bacterial sinusitis.

Comparative study of the clinical effectiveness of a pyrethrin-based pediculicide with combing versus a permethrin-based pediculicide with combing.

In a randomized, evaluator-blinded clinical trial, 190 patients were treated for Pediculus humanus capitis infestations with a pyrethrin-piperonyl-butoxide pediculicide (RID; Py-PB) and a permethrin pediculicide (NIX; PM). A total of 160 patients were evaluable for nit-combing speed, 156 patients were evaluable for efficacy at day 7, and 150 patients were evaluable for efficacy at day 14. Both Py-PB and PM showed 100% efficacy at day 7. At day 14, one patient in the PM group had an apparent reinfestation. The Py-PB group had significantly lower mean combing times (P=0.04), but because the PM group had more nits, the two groups were not significantly different in combing speed expressed as seconds per nit. Multiple regression and covariance analyses suggested that the greater speed of the Py-PB comb might have been masked by this baseline difference. Three patients had mild adverse experiences (Py-PB: erythema, PM: erythema and tingling sensation). No patients were removed from the study because of adverse events. In conclusion, this controlled clinical study demonstrated that both Py-PB and PM provided 100% efficacy following a single application. Differences attributable to comb design favored the Py-PB "rake" comb, but this requires additional evaluation and confirmation.

Effects of therapy with recombinant human growth hormone on insulin-like growth factor system components and serum levels of biochemical markers of bone formation in children after severe burn injury.

Burn injury in children is associated with low bone formation and long-term bone loss. Because recombinant human GH (rHGH) may accelerate burn wound healing, and because rHGH increases bone formation and density in GH-deficient patients, we studied the short-term effects of rHGH on bone fomation, reflected by osteocalcin and type I procollagen propeptide levels in a randomized, double-blind, placebo-controlled study. Nineteen patients were enrolled and received either rHGH (0.2 mg/kg.day) or an equal volume of saline. Mean burn size and age were not different between the groups, and test substances were given from admission to time of wound healing (mean: 43 +/- 22 days). At wound healing, serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in the rHGH group rose to mean values of 229% and 187% of the respective means of the placebo group (P < 0.025). Serum osteocalcin concentrations remained below normal in both groups, and type I procollagen propeptide levels achieved a low normal level IGFBR-4 levels were twice that of normal on admission and doubled further at wound healing; IGFBP-5 levels were low on admission but rose to normal at wound healing. We conclude that large doses of rHGH were ineffective in improving disordered bone formation despite increasing serum IGF-1 and IGFBP-3. The rHGH-independent rise in serum levels of the inhibitory binding protein IGFBP-4 suggests a mechanism by which improved bone formation is prevented despite successful elevation of IGF-1 and IGFBP-3 in the burned child.

Metabolic bone disease of total parenteral nutrition.

Parenteral nutrition-associated metabolic bone disease in children is manifested primarily as osteopenia and, on occasion, fractures. The etiology is likely multifactorial, with calcium and phosphate deficiency playing a major role in the preterm infant and with the role of aluminum toxicity yet to be clearly defined in this population. Lack of normal values of bone histomorphometry in the premature infant as well as lack of normal data for biochemical markers of bone turnover in these patients contribute to the uncertainty. Other factors that may play a role in the pathogenesis include lack of periodic enteral feeding; underlying intestinal disease, including malabsorption and inflammation; the presence of neoplasms; and drug-induced alterations in calcium and bone metabolism. The true incidence and prevalence of parenteral nutrition-associated bone abnormalities in pediatric patients remain unknown.

Dysregulation of calcium homeostasis after severe burn injury in children: possible role of magnesium depletion.

OBJECTIVE: To determine the cause and extent of hypocalcemia observed in children after severe burns. DESIGN: We studied 10 children with burns covering 57% +/- 17% (SD) body surface area, ages 9.6 +/- 4.7 years, who were admitted consecutively during a 6-month period. Diet supplied a minimum of 2.7 gm/m2 of calcium, 0.3 gm/m2 of magnesium, and 2.2 gm/m2 phosphate. Blood specimens were obtained daily for 10 +/- 5 days for the following tests: (1) simultaneous analysis for ionized calcium, magnesium, and intact parathyroid hormone (group A); (2) two of these children, randomly selected, had serial 2-hour determinations on a single day (group B); (3) a modified Ellsworth-Howard test, consisting of a 10-minute infusion of synthetic parathyroid hormone 18 +/- 10 days post-burn and associated changes in urinary cyclic adenosine monophosphate excretion and renal threshold phosphate concentration (group C). Three of these children, when normomagnesemic, also received a standard magnesium infusion to determine magnesium retention (group D). Data were analyzed with chi-square, regression analysis, and non-parametric testing as appropriate. RESULTS: All patients showed sustained hypocalcemia and hypomagnesemia; intact parathyroid hormone response was inappropriately low and response to synthetic parathyroid hormone infusion was blunted. Lowest ionized calcium levels were associated with hypomagnesemia. CONCLUSION: Hypoparathyroidism and blunted renal response to parathyroid hormone suggest that magnesium depletion may contribute to their pathogenesis. Magnesium repletion and monitoring are recommended.

Nutrition and health for older persons in rural America: a managed care model.

Health care services and resources for older persons living in rural areas may be highly variable, and integrated service-delivery models are often lacking. This article presents a managed-care model of nutrition risk screening and intervention for older persons in rural areas. Nutrition risk screening was implemented by the Geisinger Health Care System, Danville, Pa, to target all eligible enrollees in a regional Medicare risk program. A single remote clinic site participating in the managed health care system was chosen for further study of a linked screening and case-management effort for undernourished persons. Screening and intervention at the clinic site selected for this study were guided by centralized expertise and resources. Individualized evaluation and intervention plans were developed with the aid of a dietitian and implemented by the clinic case manager. Of the 417 subjects who completed screening at the remote site, 68 met the risk criteria for undernutrition and were selected for case management. Many of the targeted persons received interventions that included evaluations by a physician or physician extender (eg, physician assistant, nurse practitioner) at the clinic and consultations with nutrition, mental health, or social services professionals. Twenty-six of the subjects who took part in the intervention completed a follow-up screening 6 months later. Ten of those persons no longer exhibited risk criteria. This demonstrates the feasibility of a linked screening and case management program for nutrition risk in the managed-care setting.

The management of acute bone loss in severe catabolism due to burn injury.

Reduced bone formation has been documented in both children and adults following burn injury of > or = 40% total body surface area. In children, reduced bone formation and hypercalciuria may be the underlying causes of acute and sustained reduction in bone mineral density. The possible consequences of this reduction are an increase in extrapolated annual fracture incidence and reduced peak bone mass. Excessive endogenous glucocorticoid production, immobilization, bone marrow suppression, and magnesium depletion are all postulated as underlying causes. The most promising potential management agent is recombinant human growth hormone, which can stimulate bone formation via production of insulin-like growth factor I(IGF-I) and its associated binding protein, IGFBP-3, which correlates with bone mineral density in adults. Long-term treatment may be necessary to see a positive effect on bone formation and bone density. Correcting any detected magnesium depletion, and exercise as tolerated, are two other management strategies that might improve bone formation in this population.

Brompheniramine, terfenadine, and placebo in allergic rhinitis.

BACKGROUND: Second-generation antihistamines, reported to lack central nervous system depressant activity, may be considered to have a clinical advantage over traditional antihistamines. OBJECTIVE: To compare the effectiveness, at recommended doses, of an extended-release formulation of nonprescription brompheniramine and prescription terfenadine in the treatment of allergic rhinitis. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter, parallel study. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg (n = 96), terfenadine 60 mg (n = 96), or placebo (n = 95) twice daily for 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, the investigator assessed symptom severity (i.e., rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). The investigator and the subject each completed a global efficacy evaluation, and subjects were interviewed regarding the occurrence of adverse experiences. Symptoms were analyzed as summed severity scores for (1) all symptoms and (2) for the symptom cluster of rhinorrhea, sneezing, and nasal blockage. RESULTS: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P < or = .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. Terfenadine was significantly better (P < or = .05) than placebo on the physician's global at day 14. Central nervous system-related complaints were the most frequently reported adverse experiences among all three groups; somnolence was reported most frequently by brompheniramine-treated subjects. CONCLUSION: A nonprescription, extended-release formulation of brompheniramine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitis than terfenadine, 60 mg bid.

Burn-associated bone disease in sheep: roles of immobilization and endogenous corticosteroids.

To determine the role of immobilization in the pathogenesis of burn-associated bone disease, we selected the sheep as a model to study the effects of burn injury compared with a sham-burned control group. Seven of the sheep were subjected to controlled 40% flame burn, and seven underwent anesthesia with arterial and venous cannulation but without burn. After labeling newly formed bone with tetracycline and calcein, the sheep were killed 2 weeks after burn or sham burn, and the iliac crest and lumbar vertebrae were analyzed for histomorphometry. Analysis failed to demonstrate a significant reduction of bone formation rate in the burned sheep. Osteoid area and surface and osteoblast surface, which correlated significantly with bone formation rate (r = 0.49, p < 0.025), were reduced in the burned sheep. Results suggest that immobilization may play a primary role in the pathogenesis of burn-associated bone disease, but the presence of differences in other histomorphometric features indicates the bone disease is multifactorial.

Histomorphometric and biochemical characterization of bone following acute severe burns in children.

Severe burns in adults is associated with an uncoupling of normal remodeling, low bone formation without reduced resorption. The risk of osteopenia that may occur under such circumstances is heightened by our detection in a cross-sectional study of low bone mass in severely burned children. We report here the acute histomorphometric and biochemical response of bone to severe burn injury, as well as bone mass in severely burned children. We enrolled 24 patients ages 5.8 to 17.5 years following burns of 63 +/- 16% (SD) body surface area. Serum and urine were collected weekly until iliac crest bone biopsy was obtained 26 +/- 10 days postburn. Seventeen of 18 patients, including 5 patients receiving growth hormone treatment to accelerate wound healing, failed to take up doxycycline in trabecular bone, and had no detectable osteoblasts at the osteoid seam, while eroded surface was normal and osteoblasts were documented by staining. Thus, bone formation was virtually absent. There was an eightfold elevation in urinary free cortisol excretion and high serum levels of acute phase reactants and interleukin-1 beta and -6. Biochemical markers of bone formation, osteocalcin, and type I procollagen propeptide were low, as were resorptive markers urinary pyridinoline and deoxypyridinoline. However, there was no correlation with resorptive surface. Mean age-related z-score for bone mass was -1.06 +/- 1.05, 40 days postburn. Immobilization and endogenous corticosteroid production may be the main factors responsible for acutely reduced bone formation while inflammatory cytokines may mediate resorption.